For many bacteria, life cycles between dormancy and activity, and we have recently advanced a new model for the switch between these states. We proposed that dormancy exit is not a response to environmental cues, a characteristic of microbial spores, resting seeds of plants, hibernating animals, among others, but a low frequency, epigenetic, noise-driven, and stochastic process. After awakening, the cells termed "scouts" explore whether or not the environmental conditions are appropriate for growth. The scout strategy guarantees the continued existence of even the smallest population under conditions of environmental challenge, and becomes a particularly important characteristic of pathogenic populations in human body. We present strong evidence that at least some non-spore forming species, such as Mycobacterium smegmatis, and a range of environmental isolates do behave in accordance with the scout model. We show that cells of tested species can remain dormant for weeks and months, wake up from dormancy at dramatically different time points, and after establishing a small proliferating population, produce growth inducing compounds that revive their dormant kin. In this project, we will examine the kinetics of the awakening process and elucidate the chemical nature of the growth inducing factor(s). The gained knowledge will be used in the future to study the biology of slow growing pathogens such as Mycobacterium tuberculosis. This may ultimately lead to better tools for disease control, and is especially relevant to latent infections.

Public Health Relevance

Microbes survive unfavorable conditions in the environment (e.g., starvation) or human body (e.g. antibiotic treatment) in a non-growing or dormant state. This project will establish the molecular basis through which microbial cells wake up from dormancy based on a model that exit occurs through stochastic awakening of a few cells, or via induction by growing kin. This understanding can lead to improved disease control, especially of latent infections, and provide alternative interpretations to several general microbiological phenomena.